A concise synthesis of eupomatilones 4, 6, and 7 by rhodium-catalyzed enantioselective desymmetrization of cyclic meso anhydrides with organozinc reagents generated in situ

Article abstract of DOI:10.1002/anie.200700816

The wages of syn: The development of a phosphoramidite-ligated rhodium catalyst allows the enantioselective desymmetrization of cyclic anhydrides with organozinc nucleophiles formed in situ. This methodology has been utilized for a concise synthesis of eupomatilones 4 and 7 and of the putative structure of eupomatilone 6, each of which is completed in four steps in greater than 50% overall yield.

Full text of DOI:10.1002/anie.200700816

Communications
DOI: 10.1002/anie.200700816
Enantioenriched Keto Acids
A Concise Synthesis of Eupomatilones 4, 6, and 7 by Rhodium-
Catalyzed Enantioselective Desymmetrization of Cyclic meso
Anhydrides with Organozinc Reagents Generated In Situ**
Jeffrey B. Johnson, Eric A. Bercot, Catherine M. Williams, and Tomislav Rovis*
Cross-coupling methodology, as a subset of transition-metal-
catalyzed reactions, has revolutionized the means by which
complex molecules are constructed.[1] Despite recent advan-
ces, significant challenges remain in this area, including the
selective construction and definition of stereocenters.[2]
Although numerous activated acyl species have been utilized
in the formation of ketones,[3] carboxylic acid anhydrides have
only recently been investigated as acylating agents in metal-
mediated reactions.[4] Our group is engaged in the develop-
ment of the transition-metal-catalyzed cross-coupling reac-
tions of carboxylic anhydrides and has reported the nickel-
catalyzed alkylation of cyclic anhydrides with organozinc
nucleophiles to produce 1,4- or 1,5-keto acids.[5]
The power of this methodology lies in the ability to
transform cyclic carboxylic anhydrides into keto acid deriv-
atives with stereodefined backbones. We have recently
disclosed the enantioselective desymmetrization of succinic
anhydrides catalyzed by Pd(OAc)2 and Josiphos (1)
(Scheme 1).[6] As part of an effort to utilize this reaction for
the rapid assembly of complex molecules, we targeted the
enantioselective desymmetrization of 2,3-dimethylsuccinic
anhydride utilizing functionalized organozinc nucleophiles.
Despite the excellent results obtained with commercially
available diorganozinc reagents, the use of zinc nucleophiles
formed in situ is not compatible with the palladium-catalyzed
methodology, an observation not uncommon in asymmetric
catalysis involving organozinc reagents.[7,8] Organozinc nucle-
ophiles also fail to produce the desired keto acids in
appreciable yields, further limiting the number of available
nucleophiles.
Rhodium complexes have been documented to tolerate
the presence of Lewis bases, as illustrated by rhodium-
catalyzed asymmetric conjugate addition reactions run in
water,[9] and thus they promise to be less susceptible to
complications arising from the presence of halides. Further-
more, the use of the RhI/RhIII redox couple holds the promise
of a mechanism distinct from that of the nickel- and
palladium-catalyzed reactions.[10] Herein, we present the
development of the rhodium-catalyzed desymmetrization of
succinic anhydrides with a variety of zinc nucleophiles formed
in situ. The utility of this methodology is demonstrated with
the concise synthesis of three members of the eupomatilone
family of natural products.
Organozinc nucleophiles, formed from the corresponding
arylbromide by lithium–halogen exchange and subsequent
reaction with various ZnX2 salts, were utilized in the
identification of RhI sources capable of catalyzing the
addition to cyclic carboxylic anhydrides (Table 1). Further
screening revealed the currently optimized conditions for the
enantioselective desymmetrization of meso succinic anhy-
drides: [{Rh(cod)Cl}2] (4 mol%) (cod = cyclooctadiene),
used in conjunction with phosphoramidite ligand
2
(8 mol%), catalyzes the coupling of ArZnOTf nucleophile 3
(1.4 equiv) with dimethylsuccinic anhydride 4 (1 equiv) in
DMF at 508C over 16 h. These conditions provide the
corresponding keto acid, 5, in 85% yield and 87% ee.[11]
Table 1 illustrates the impact of changing several components
of these standard conditions. While the reaction proceeds in a
number of different solvents and with numerous ZnX2 salts,
all alternatives to DMF and Zn(OTf)2 produce inferior
results.
In addition to representing the first example of the
application of organozinc reagents formed in situ in the
enantioselective desymmetrization of anhydrides, it is also
notable that optimum conditions include the use of ArZnOTf
nucleophiles. Formation of these nucleophiles requires only a
single equivalent of the aryl lithium precursor. This con-
stitutes a significant advance over earlier studies that often
required the more reactive diorganozinc reagents, which
results in the transfer of only one of the two zinc substitu-
ents.[12]
Scheme 1. Palladium-catalyzed enantioselective desymmetrization of
succinic anhydrides. Tf=trifluoromethanesulfonyl.
[*] Dr. J. B. Johnson, E. A. Bercot, C. M. Williams, Prof. T. Rovis
Department of Chemistry
Colorado State University
Fort Collins, CO 80523 (USA)
Fax: (+1)970-491-1801
E-mail: rovis@lamar.colostate.edu
[**] We thank Johnson and Johnson, Merck, Eli Lilly, and Boehringer-
Ingelheim for support. T.R. thanks the Monfort Family Foundation
for a Monfort Professorship. T.R. is a fellow of the Alfred P. Sloan
Foundation. J.B.J. thanks the NIH for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 1: Optimization of conditions for the rhodium-catalyzed desym-
metrization of cis-2,3-dimethylsuccinic anhydride.
Table 2: Anhydride scope.
Entry[a]
Anhydride
Product
Yield [%]
85
ee [%][b]
1
7
87
Entry
Deviation from standard conditions[a]
Yield [%]
ee [%][c]
2
9
11
13
15
72
77
61
56
83
82
77
76
1
2
3
4
5
6
7
8
9
no change
85
68
<10
58
73
74
71
32
30
23
87
47
–
THF, instead of DMF
toluene, instead of DMF
258C, instead of 508C
808C, instead of 508C
ZnCl2, instead of Zn(OTf)2
ZnBr2, instead of Zn(OTf)2
ZnI2, instead of Zn(OTf)2
ArLi/Zn(OTf)2 2:1
70
74
78
72
60
68
32
42
46
3
4[c]
10
11
12
iPr-Phox[b] (6), instead of 2
Taddol-PNCy2 (7) instead of 2
[Rh(cod)2]BF4
32
76
5[c]
[a] Standard conditions: Anhydride 4 (1 equiv) and ArZnOTf (1.4 equiv)
with[{Rh(cod)Cl} 2] (4 mol%) and ligand 2 (8 mol%) in DMF at 508C for
20 h. [b] iPr-Phox (6)=isopropylphosphinooxazoline. [c] Determined by
HLPC of corresponding methyl ester utilizing a chiral stationary phase.
[a] Standard reaction conditions. [b] Determined by HLPC of correspond-
ing methyl ester utilizing a chiral stationary phase. [c] Reactions run at
258C.
To further extend the utility of this methodology, standard
reaction conditions were utilized to examine the reactivity of
a series of cyclic meso succinic anhydrides (Table 2).[13]
Various anhydrides are compatible in this chemistry, includ-
ing substrates that possess backbone olefins and strained
rings. Although enantioselectivities in this reaction are
slightly diminished relative to those observed with the Pd/
Josiphos methodology, the scope is equally diverse, tolerating
a range of succinic anhydrides.
The strength of this methodology is demonstrated with the
scope of the organozinc nucleophiles, which was determined
to be quite general (Table 3). The arylzinc triflate nucleo-
philes are formed from the reaction of the nucleophile
precursor with nBuLi or tBuLi, and the corresponding aryl
lithium species is subsequently added to a suspension of
Zn(OTf)2 in THF. Following a solvent switch to DMF, these
nucleophiles are utilized in the desymmetrization method-
ology without isolation or additional purification. Noteworthy
is that no effort is made to liberate the organozinc triflate
nucleophile from any salt byproducts—all components
remain present, yet have no deleterious influence upon the
asymmetric reaction. The functional-group tolerance of this
reaction is illustrated by the use of arylzinc triflates formed
from a series of functionalized aryl bromides, as well as
products formed from 2-methylfuran (26), dihydropyran (28)
and N-methylindole (30) (entries 6–8, Table 3).[14] Yields
range from 74 to 88%, and enantioselectivities are typically
greater than 85% ee. It is notable that the enantioselectivity is
quite similar for most nucleophiles, suggesting that the
enantioselectivity-determining step occurs independently of
nucleophile involvement.
To demonstrate the synthetic utility of the asymmetric
desymmetrization methodology, we sought to prepare three
members of the eupomatilone family of lignans. Eupomati-
lones 1–7, natural products isolated from the Australian shrub
Eupomatia bennettii, are a structurally unique subset of the
broader lignan family.[15] These species are characterized by
highly oxygenated biaryl systems connected to a trisubstituted
g-lactone core. While several members of this family have
been prepared in racemic form,[16,17] only recently have the
research groups led by Buchwald and Gurjar accomplished
the asymmetric synthesis of eupomatilone lignans.[18,19] We
envisioned that our desymmetrization methodology could be
utilized to develop a general, asymmetric approach to the
synthesis of eupomatilone 4, eupomatilone 7, and the origi-
nally assigned structure of eupomatilone 6.
The syn-dimethyl relationship present in the backbone of
the eupomatilones can be readily accessed by the coupling of
the appropriate arylzinc triflate with cis-dimethyl succinic
anhydride (4). Substrate-controlled reduction of the resulting
keto acid followed by cyclization results in the formation of
the desired all-syn lactone.[20] Subsequent biaryl installation
by a halogenation/Suzuki-coupling sequence then provides
ready access to these three natural products. This route
presents numerous attractive features, including rapid assem-
bly of the stereochemically complex core and a structurally
flexible sequence in which each component can be tailored
for the desired product.
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Table 3: Nucleophile scope.
Entry[a] Nucleophile
precursor
Product
Yield [%] ee [%][b]
1
2
85
88
87
88
Scheme 2. Core synthesis of eupomatilones 4 and 7. DIBAL-H=diisobutyl-
aluminum hydride, TFA=trifluoroacetic acid, NBS=N-bromosuccinimide.
3
4
75
74
85
87
5
78
87
6
7
8
82
76
84
85
80
86
Scheme 3. Completion of eupomatilones 4 and 7. DME=dimethoxy-
ethane.
[a] Standard reaction conditions [b] Determined by HPLC of correspond-
ing methyl ester using a chiral stationary phase.
Suzuki coupling of 3,4-dimethoxyphenylboronic acid (35)
with 32 provides eupomatilone 7 (36) as a 1:1 mixture of
atropisomers in 85% yield, and an overall yield of 52% in
four steps.[24] The lactone core of eupomatilones 4 and 7
contains 3R,4S,5R absolute stereochemistry which was deter-
mined through correlation with the previously reported
crystallographic analysis of keto acid 11.[6] This work repre-
sents the first asymmetric synthesis of eupomatilone 4 and the
first synthesis of any type for eupomatilone 7.
The initially proposed structure of eupomatilone 6 was
prepared in an analogous manner (Scheme 4). Coupling of
the arylzinc triflate from 16 with cis-dimethylsuccinic anhy-
dride 6 proceeds in 85% yield and 87% ee to form keto acid 7.
Diastereoselective reduction and cyclization of 7 provides g-
lactone 37 in 91% yield and in a 98:2diastereomeric ratio.
Iodination of 37 was accomplished by treatment with I2 in the
presence of a silver salt, providing aryl iodide 38 in 89% yield.
Suzuki coupling of boronic acid 39 under Pd catalysis
proceeded in 87% yield, providing 40, the putative structure
The syntheses of eupomatilones 4 and 7 followed the
same sequence, which began with the preparation of keto acid
18, in 88% yield and 88% ee, on a 250-mg scale using the
methodology described above (Scheme 2). Using Frenetteꢀs
protocol,[20] treatment of 18 with 2.4 equiv of DIBAL-H at
À788C produced the hydroxy acid, which was cyclized with
TFA to produce the desired all-syn lactone 31 in 82% yield in
a 97:3 ratio of diastereomers. Bromination of electron-rich
aromatic 31 was accomplished by treatment with NBS in
CHCl3 at 238C, providing aryl bromide 32 as the exclusive
regioisomer.[21]
Suzuki cross-coupling of 32 was performed using [Pd-
(PPh3)4] in refluxing DME/H2O (10:1) in the presence of
NaHCO3.[22] Use of 3,4,5-trimethoxyphenylboronic acid (33)
provides the coupling product, eupomatilone 4 (37), in 90%
yield[23]—an overall yield of 55% in four steps from readily
available starting materials 4 and 17 (Scheme 3). Similarly,
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[1] F. Diederich, P. J. Stang, Metal-Catalyzed Cross-Coupling Reac-
tions, Wiley-VCH, Weinheim, 1998.
[2] For asymmetric cross-coupling reactions, see: T. Hayashi, J.
Organomet. Chem. 2002, 653, 41, and references therein.
[3] Use of: acid chlorides: a) M. Kosugi, Y. Shimizu, T. Migita,
Chem. Lett. 1977, 6, 1423; b) D. Milstein, J. K. Stille, J. Am.
Chem. Soc. 1978, 100, 3636; c) D. Milstein, J. K. Stille, J. Org.
Chem. 1979, 44, 1613; thioesters: d) H. Tokuyama, S. Yokosh-
ima, T. Yamashita, T. Fukuyama, Tetrahedron Lett. 1998, 39,
3189; e) L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122,
11260; f) R. Wittenberg, J. Srogl, M. Egi, L. S. Liebeskind, Org.
Lett. 2003, 5, 3033; aryl trifluoroacetates: g) R. Kakino, I.
Shimizu, A. Yamamoto, Bull. Chem. Soc. Jpn. 2001, 74, 371; acyl
cyanides: h) C. Duplais, F. Bures, I. Sapountzis, T. J. Korn, G.
Cahiez, P. Knochel, Angew. Chem. 2004, 116, 3028; Angew.
Chem. Int. Ed. 2004, 43, 2968; acid fluorides: i) Y. Zhang, T.
Rovis, J. Am. Chem. Soc. 2004, 126, 15964.
[4] a) S. D. Real, D. R. Kronenthal, H. Y. Wu, Tetrahedron Lett.
1993, 34, 8063; b) L. J. Goossen, K. Ghosh, Angew. Chem. 2001,
113, 3566; Angew. Chem. Int. Ed. 2001, 40, 3458; c) C. G. Frost,
K. J. Wadsworth, Chem. Commun. 2001, 2316; d) R. Shintani,
G. C. Fu, Angew. Chem. 2002, 114, 1099; Angew. Chem. Int. Ed.
2002, 41, 1057; e) R. Kakino, S. Yasumi, I. Shimizu, A.
Yamamoto, Bull. Chem. Soc. Jpn. 2002, 75, 137; f) D. Wang, Z.
Zhang, Org. Lett. 2003, 5, 4645; g) Y.-T. Hong, A. Barchuk, M. J.
Krische, Angew. Chem. 2006, 118, 7039; Angew. Chem. Int. Ed.
2006, 45, 6885.
Scheme 4. Synthesis of 3-epi-eupomatilone 6. Tol=toluene.
[5] a) E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2002, 124, 174;
b) E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2005, 127, 247;
c) J. B. Johnson, R. T. Yu, P. Fink, E. A. Bercot, T. Rovis, Org.
Lett. 2006, 8, 4307; d) J. B. Johnson, E. A. Bercot, J. M. Rowley,
G. W. Coates, T. Rovis, J. Am. Chem. Soc. 2007, 129, 2718.
[6] E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2004, 126, 10248.
[7] For a recent solution to this problem in the addition of diarylzinc
reagents to aldehydes, see: J. G. Kim, P. J. Walsh, Angew. Chem.
2006, 118, 4281; Angew. Chem. Int. Ed. 2006, 45, 4175.
[8] Control experiments revealed that the presence of LiX led to
drastically lower enantioselectivity even with Ph2Zn as the
nucleophile.
of eupomatilone 6, in four steps from 4 and 16 in 60% overall
yield.[25]
As previously described by Gurjar et al.[19] and Coleman
et al.,[17c] this structure is in fact 3-epi-eupomatilone 6, which
contains the 3R,4S,5R backbone sequence. Natural eupoma-
tilone 6, which contains the 3S,4S,5R sequence, can be
obtained from this material by subjection of 40 to 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene and
separation of the resulting epimers.[19]
Herein, we have described the enantioselective rhodium-
catalyzed cross-coupling of meso cyclic carboxylic anhydrides
with arylzinc reagents and the total syntheses of three
members of the eupomatilone family of lignan natural
products. The cross-coupling reaction proceeds with selectiv-
ities in excess of 80% ee with a variety of nucleophiles formed
from corresponding lithium reagents and used without
purification. Synthetic routes, which include the definition
or construction of three contiguous stereocenters with
excellent control, have been developed for eupomatilones 4
and 7, as well as the originally proposed structure of
eupomatilone 6. Each species is prepared in a concise four-
step sequence with greater than 50% overall yield. The
flexible synthetic route provides rapid stereoselective forma-
tion of the g-lactone core and allows ready manipulation of
the biaryl functionality.
[9] T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829, and
references therein.
[10] Rh complexes have been demonstrated to catalyze the addition
of aryl boronic acids and vinyl silanes to anhydrides, see:
a) reference [4c]; b) M. Yamane, K. Uera, K. Narasaka, Bull.
Chem. Soc. Jpn. 2005, 78, 477; c) M. Yamane, K. Uera, K.
Narasaka, Chem. Lett. 2004, 33, 424.
[11] The absolute configuration of keto acid 7 was determined by
analogy to the configuration of 11, which was previously
determined. See reference [6].
[12] For leading references on solutions to this problem, see: a) C.
Lutz, P. Knochel, J. Org. Chem. 1997, 62, 7895; b) C. Lutz, P.
Jones, P. Knochel, Synthesis 1999, 312.
[13] It should be noted that acyclic anhydrides were not tested under
these conditions, as similar reactivity is accessible utilizing less
expensive catalysts. See reference [4].
[14] Under these conditions, aliphatic nucleophiles are not compat-
ible. For example, BuLi and BnLi (BnBr/tBuLi) each provide
trace amounts of product and complex reaction mixtures.
[15] a) A. R. Carroll, W. C. Taylor, Aust. J. Chem. 1991, 44, 1615;
b) A. R. Carroll, W. C. Taylor, Aust. J. Chem. 1991, 44, 1705.
[16] a) S.-p. Hong, M. C. McIntosh, Org. Lett. 2002, 4, 19; b) J. M.
Hutchison, S.-p. Hong, M. C. McIntosh, J. Org. Chem. 2004, 69,
4185.
Received: February 22, 2007
Published online: May 11, 2007
Keywords: cross-coupling · homogeneous catalysis ·
phosphoramidites · rhodium · total synthesis
[17] a) S. H. Yu, M. J. Ferguson, R. McDonald, D. G. Hall, J. Am.
Chem. Soc. 2005, 127, 12808; b) G. W. Kabalka, B. Venkataiah,
.
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Communications
Tetrahedron Lett. 2005, 46, 7325; c) R. S. Coleman, S. R. Gurrala,
Org. Lett. 2004, 6, 4025.
[21] B. M. Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117, 10143.
[22] For a review of Suzuki coupling for the formation of biaryls, see:
A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350; Angew.
Chem. Int. Ed. 2002, 41, 4176.
[18] Eupomatilone 3: M. P. Rainka, J. E. Milne, S. L. Buchwald,
Angew. Chem. 2005, 117, 6333; Angew. Chem. Int. Ed. 2005, 44,
6177.
[19] 3-epi-Eupomatilone 6: a) M. K. Gurjar, J. Cherian, C. V.
Ramana, Org. Lett. 2004, 6, 317; Eupomatilone 6: b) M. K.
Gurjar, B. Karumudi, C. V. Ramana, J. Org. Chem. 2005, 70,
9658.
[20] a) R. Frenette, M. Kakushima, R. Zamboni, R. N. Young, T. R.
Verhoeven, J. Org. Chem. 1987, 52, 304; b) R. Frenette, M.
Monette, M. A. Bernstein, R. N. Young, T. R. Verhoeven, J. Org.
Chem. 1991, 56, 3083; c) E. A. Bercot, D. E. Kindrachuk, T.
Rovis, Org. Lett. 2005, 7, 107.
[23] Eupomatilone 4 (34, 88% ee): [a]D = + 23.6 degcm3 gÀ1 dmÀ1
(c = 0.4 gcmÀ3
,
CHCl3),
+ 36.4 degcm3 gÀ1 dmÀ1 (c = 0.5 gcmÀ3, CHCl3).
[24] Eupomatilone 7 (36, 88% ee): [a]D = + 24.3 degcm3 gÀ1 dmÀ1
Lit.:
Ref. [15b];
[a]D =
(c = 0.6 gcmÀ3
+ 35.8 degcm3 gÀ1 dmÀ1 (c = 0.5 gcmÀ3, CHCl3).
,
CHCl3),
Lit.:
Ref. [15b];
[a]D =
[25] 3-epi-Eupomatilone 6
(40,
87% ee):
[a]D =
+ 24.8 degcm3 gÀ1 dmÀ1 (c = 0.6 gcmÀ3, CHCl3), Lit.: Ref. [19a];
[a]D = + 30.0 degcm3 gÀ1 dmÀ1 (c = 0.5 gcmÀ3, CHCl3).
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